The objective of this project is the investigation of purine metabolism in gout and in neoplastic disease; the elucidation of the causes for purine overproduction; and the examination of the pharmacologic regulation of purine biosynthesis in man. Purine synthesis de novo and by the "salvage" pathway will be studied in peripheral leukocytes in vitro of leukemic and gouty patients, and in cultured lymphocytes of these patients. The characteristics of the enzyme activities which catalyze the synthesis of the first intermediate of the purine biosynthetic pathway will be studied in enzyme preparations from peripheral leukocytes of leukemia patients and in cultures lymphocytes of selected gouty subjects. The correlation between the pharmacologic regulation of purine metabolism in intact cells and in cell free enzyme preparations will yield pertinent information on the understanding and treatment of gout and myeloproliferative diseases. The role of ammonia in purine biosynthesis de novo will also be defined in these studies. The activity of the purine biosynthetic enzymes is stimulated in hematopoietic tissues in experimental leukemia, and in peripheral leukocytes in the acute phase of chronic myelocytic leukemia in man, and therefore may reflect changes in gene expression in malignant disease. Factors which control cellular differentiation will be studied in cells maintained in tissue culture; the source of material for these studies will include human lymphcoyte cell lines of patients with genetic diseases of purine metabolism and leukemia; a cell line cloned from spleens of mice infected with Friend leukemia virus, and a neuroblastoma cell line with a genetic abnormality in purine metabolism. Modulation of gene expression and the factors which control gene functions will be studied in these model systems. Changes in specialized cell functions will be correlated with changes in the activity of the enzymes of purine metabolism.